[1,8] naphthyridine derivatives having antiviral activity

ABSTRACT

The present invention is concerned with novel [1,8] naphthyridine derivatives useful for the inhibition of the hepatitis virus, more specifically the hepatitis C virus.

FIELD OF THE INVENTION

[0001] The present invention relates to heterocyclic compounds, morespecifically derivatives of [1,8] naphthyridine, useful for theinhibition of viral infections.

BACKGROUND OF THE INVENTION

[0002] Hepatitis is a disease occurring throughout the world, It isgenerally of viral nature, although there are other causes known. Viralhepatitis is by far the most common form of hepatitis. Nearly 750,000Americans are affected by hepatitis each year, and out of those, morethan 150,000 are infected with the hepatitis C virus (“HCV”)

[0003] HCV is a positive-stranded RNA virus belonging to theFlaviviridae family and has closest relationship to the pestivirusesthat include hog cholera virus and bovine viral diarrhea virus (BVDV).HCV is believed to replicate through the production of a complementarynegative-strand RNA template. Due to the lack of efficient culturereplication system for the virus, HCV particles were isolated frompooled human plasma and shown, by electron microscopy, to have adiameter of about 50-60 nm. The HCV genome is a single-stranded,positive-sense RNA of about 9,600 bp coding for a polyprotein of3009-3030 amino-acids, which is cleaved co and post-translationally bycellular and two viral proteinases into mature viral proteins (core, E1,E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). It is believed thatstructural proteins, E1 and E2, the major glycoproteins are embeddedinto a viral lipid envelope and form stable heterodimers. The structuralcore protein interacts with the viral RNA genome to form thenucleocapsid. The nonstructural proteins designated NS2 to NS5 code forproteins with enzymatic functions involved in virus replication andprotein processing including a polymerase, protease and helicase.

[0004] The main sources of contamination with HCV is blood. Themagnitude of the HCV infection as a health problem is illustrated by theprevalence among high-risk groups. For example, 60% to 90% ofhemophiliacs and more than 80% of intravenous drug abusers in westerncountries are chronically infected with HCV. For intravenous drugabusers, the prevalence varies from about 28% to 70% depending on thepopulation studied. The proportion of new HCV infections associated withpost-transfusion has been markedly reduced lately due to advances indiagnostic tools used to screen blood donors.

[0005] The only treatment currently available for HCV infection isinterferon-α (IFN-α), either as monotherapy and in combination withribavirin. However, according to different clinical studies, only 70% oftreated patients normalize alanine aminotransferase (ALT) levels in theserum and after discontinuation of IFN, 35t to 45% of these respondersrelapse. In general, only 40% of patients have long-term responses toIFN/ribavirin combination therapy. On the other hand, pilot studiessuggest that combination treatment with IFN plus Ribavirin (RIBA)results in sustained response in the majority of patients. Differentgenotypes of HCV respond differently to IFN therapy, genotype 1b is moreresistant to IFN therapy than type 2 and 3.

[0006] In spite of advances in the knowledge of HCV replication andtransmission, it therefore appears that to this date, no effectiveuniversal treatment of HCV is available. This is due in great part tothe fact that only humans and chimpanzees can be infected with thevirus. Consequently, there are no in vivo animal models for testingpotential therapeutic agents and thus, no vaccine available forhepatitis C. Another factor preventing the development of in vivo assaysis that human liver tissue is difficult to obtain and is expensive,thereby preventing its use in large scale screening where largequantities of tissue would be needed. Combined with the prohibitive costand availability of chimpanzees, in vivo models are presently notamenable for screening purposes.

[0007] Jin et al. described [1,6] naphthyridine derivatives useful asinhibitors of human cytomegalovirus (HCMV). A [1,8] naphthyridinederivative was also identified as having such inhibiting activity,though to lesser extent, i.e. [1,8] naphthyridine-2-carboxylic acid2-methoxybenzyl-amine. However, no other use is suggested for thisparticular compound. There is therefore a great need for the developmentof a hepatitis virus inhibitor, and particularly HCV.

[0008] The herpes group of viruses which includes Epstein-Barr virus(EBV), varicella Zoster virus (VZV), Herpes Simplex viruses (HSV-1,HSV-2) and Human Herpes virus (HHV6) is recognized as an importantpathogen in patients with AIDS. These viruses often contribute to theimmunosuppression observed in such patients and may cause disseminateddisease involving the lungs, gastrointestinal tract, central nervoussystem, or eyes.

[0009] All human Herpes viruses have a worldwide distribution and areamongst the most difficult human pathogens to control. Currently,considerable efforts are being directed towards the development ofvaccines and antiviral agents that will be active against Herpesviruses, particularly Herpes Simplex viruses HSV-1 and HSV-2, andvaricella Zoster virus (VZV). A number of nucleosides and nucleotidesderivatives are active against primary and recurrent HSV infection; ofthese, acyclovir is the most used drug. However, among patients withAIDS, acyclovir-resistant HSV-2 may lead to chronic progressiveinfections.

[0010] There is therefore a need for development of potent and non-toxicagents against Herpes viruses and hepatitis viruses.

SUMMARY OF THE INVENTION

[0011] In accordance with the present invention, there is provided amethod for the inhibition of a viral infection in a mammal, the methodcomprising administering to the mammal an antiviral amount of a [1,8]naphthyridine derivative of Formula I or a pharmaceutically acceptablesalt thereof;

[0012] wherein

[0013] Z₁, Z′₁, Z′₁, and Z₂ are independently H. halogen, carboxyl,amino, amidino, guanidino, nitro, OH, SH, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₅ alkoxy or C₁₋₆ heteroalkyl;

[0014] A is

[0015] X is O, NH, or S;

[0016] Y is O, S, (CH₂)_(n), O(CH₂)_(n), or S(C(H₂)_(n); with n is 0 to6;

[0017] R₁ and R₂ are independently H or C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl; or R₁ and R₂ together form a saturated or unsaturated 5 or 6member heterocycle; and

[0018] W is C₆₋₁₂ aryl, C₆₋₁₂ heteroaryl, or C₃₋₁₂ heterocycle

[0019] In accordance with the present invention, there is also provideda [1,8] naphthyridine derivative of Formula I or pharmaceuticallyacceptable salts thereof;

[0020] wherein,

[0021] A, Z₁, Z′₁, Z″₁, and Z₂ are as defined above; with the provisosthat:

[0022] 1) when; Y is CH₂, X is O, R₁, Z₁, Z₁′, Z₁″ and Z₂ are H, and Ais

[0023] then W is not 2-methoxyphenyl or 3-trifluoromethylphenyl; and

[0024] 2)when Y is (CH₂)₀, X is O, R₁, Z₁, Z₁′, Z₁″ and Z₂ are H, and Ais

[0025] then W is not phenyl, 3-trifluoromethylphenyl or 3-pyridinyl.

DETAILED DESCRIPTION OF THE INVENTION

[0026] As used in this application, the term “alkyl” represents anunsubstituted or substituted (by a halogen, nitro, aminoamidino,amidino, guanido, CONH₂, COOH, O—C₁₋₆ alkyl, O—C₂₋₆alkenyl,O—C₂₋₆alkynyl, amino, hydroxyl or COOQ, wherein Q is C₁₋₆ alkyl, C₂₋₆alkenyl, a C₂₋₆alkynyl) straight chain, branched chain, or cyclichydrocarbon moiety (e.g. isopropyl, ethyl, flurohexyl or cyclopropyl).The term alkyl is also meant to include alkyls in which one or morehydrogen atoms is replaced by an halogen, more preferably, the halogenis fluoro (e.g., CF₃—, or CF₃CH₃—).

[0027] The terms “alkenyl” and “alkynyl” represent an alkyl containingat least one unsaturated group (e.g., allyl).

[0028] The term “heteroalkyl” represents an alkyl, alkenyl, or alkynylin which a C atom which is part of the straight chain, branched chain orcyclic hydrocarbon moiety is replaced by one or more heteroatom such asoxygen, sulfur and nitrogen(e.g., ether, thiohexanoyl, thiomorpholino,isothiazole, imidazole, triazole, ethylmethylsulfone or ethylthio).

[0029] The term “heterocycle” represents a cyclic heteroalkyl(imidazole,isothiazole, or triazole)

[0030] The term “aryl” represents a carbocyclic moiety which may besubstituted(by a C₁₋₆ alkyl, C₂₋₆ alkenyl, a C₂₋₆ alkynyl, halogen,nitro, aminoamidino, amidino, guanido, CONH₂, COOR, O—C₁₋₆ alkyl,O—C₁₋₆alkenyl, O—C₂₋₆ alkynyl, amino, hydroxyl or COOQ, wherein Q isC₁₋₆ alkyl, C₂₋₆alkenyl, a C₂₋₆alkynyl) and containing at least onebenzenoid-type ring (e.g., phenyl and naphthyl).

[0031] The term “aralkyl” represents an aryl group attached to theadjacent atom by a C₁₋₆ alkyl, C₁₋₆alkenyl, or C₁₋₆alkynyl(e.g.,benzyl).

[0032] The term “aryloxy” represents an aryl or aralkyl moietycovalently bonded through an oxygen atom (e.g., phenoxy).

[0033] The term “heteroaryl” represents an aryl, aryloxy, or aralkyl inwhich a C atom which is a member of the carbocyclic moeity is replacedby at least one heteroatom (e.g., N, or S) (e.g pyridine, isoquinoline,or benzothiophene).

[0034] The term “acyl” refers to a radical derived from a carboxylicacid, substituted (by halogen (F, Cl, Br, I), C₆₋₂₀ aryl or C₁₋₆ alkyl)or unsubstituted, by replacement of the —OH group. Like the acid towhich it is related, an acyl radical may be aliphatic or aromatic,substituted (by halogen, C₁₋₅ alkoxyalkyl, nitro or OH) orunsubstituted, and whatever the structure of the rest of the moleculemay be, the properties of the functional group remain essentially thesame (e.g., acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl,trifluoroacetyl, chloroacetyl, and cyclohexanoyl).

[0035] Preferred compounds of the present invention comprise thosewherein the following embodiments are present, either independently orin combination:

[0036] Preferably, Z₁, Z₁′, Z₁″ and Z₂ are independently C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl which can be substituted with one or morehalogen, OH, carboxy, amino, guanidino, amidino, nitro, SH or CN. Morepreferably, Z₁, Z₁′, Z₁″ are independently C,_, alkyl, OH, halogen or H.

[0037] More preferably, Z₁, Z₁′, Z₁″ are independently methyl, ethyl,OH, halogen or H.

[0038] More preferably, at least one of Z₁, Z₁′, Z₁″ is H. Morepreferably, at least two of Z₁, Z₁′, Z₁″ are H.

[0039] Z₁, Z₁′, Z₁″ are most preferably H.

[0040] More preferably, Z₂ is C₁₋₆ alkyl, OH, halogen, or H.

[0041] More preferably, Z₂ is methyl, ethyl, OH, halogen, or H.

[0042] Z₂ is most preferably H.

[0043] Preferably, R₁ and R₂ are independently C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ alkynyl which is substituted by one or more C₁₋₆ alkyl, C₁₋₆ alkoxyor C₁₋₆ heteroalkyl, halogen, amino, guanidino, amidino, nitro, OR, SHor CN.

[0044] Preferably, R₁ and R₂ together form a saturated or unsaturated 5or 6 member heterocycle substituted with one or more C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy or C₁₋₆ heteroalkyl, halogen, amino,guanidino, amidino, nitro, OH, SH or CN.

[0045] More preferably, R₁ is C₁₋₆ alkyl or H.

[0046] More preferably, R₁ is methyl, ethyl or H.

[0047] R₁ is most preferably H.

[0048] More preferably, R₂ is C₁₋₆ G alkyl or H.

[0049] More preferably, R₂ is methyl, ethyl or H.

[0050] R₂ is most preferably H.

[0051] Preferably, W is C₆₋₁₂ aryl, C₆₋₁₂ heteroaryl, C₃₋₁₂ heterocycle,either of which is substituted with one or more C₁₋₆ alkyl, C₂₋₆alkenyl, C₃₋₆ alkynyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, C₁₋₆ heteroalkyl, C₁₋₆ perfluoroalkylthio, halogen,amino, guanidino, amidino, nitro, OH, COOH, SH or CN.

[0052] Preferably, W is C₆₋₁₂ aryl, C₆₋₁₂ heteroaryl, C₃₋₁₂ heterocycle,either of which is substituted with one or more C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆perfluoroalkoxy, C₁₋₆ heteroalkyl, C₁₋₆ perfluoroalkylthio, OH, COOH, SHor CN.

[0053] W is more preferably phenyl or pyridinyl unsubstituted orsubstituted with one or more C₁₋₆ alkoxy group.

[0054] W is most preferably phenyl or pyridinyl unsubstituted orsubstituted with one or more -O-methyl or O-ethyl..

[0055] Y is preferably (CH₂)_(n) and wherein n is chosen between 0 to 6.

[0056] Y is preferably (CH₂)_(n) and wherein n is chosen between 1 to 4.

[0057] Y is preferably (CH₂)_(n) and wherein n is 1.

[0058] X is preferably O.

[0059] X is preferably S.

[0060] X is preferably NH.

[0061] A is preferably

[0062] A is preferably

[0063] A is preferably

[0064] Y is preferably (CH₂)_(n) and n is 0.

[0065] Y is more preferably (CH₂)_(n) and n is 1.

[0066] Y is most preferably (CH₂)_(n) and n is 2.

[0067] Z₁, Z₁′, Z₁″ and Z₂ are preferably H.

[0068] R₁, Z₁, Z₁′, Z₁″ and Z₂ are preferably H.

[0069] In an alternative embodiment, R₁, Z₁, Z₁′, Z₁″ and Z₂ are H and Yis (CH₂)_(n) wherein n is chosen between 0 to 6. n is preferably 0.

[0070] In an alternative embodiment, X is O, R₁ is H, Z₁, Z₁′, Z₁″ are Hand Z₂ is H.

[0071] In an alternative embodiment X is S, R₁ is H, Z₁, Z₁′, Z₁″ are Hand Z₂ is H.

[0072] In an alternative embodiment X is NH, R₁ is H, Z₁, Z₁′, Z₁″ are Hand Z₂ is H.

[0073] In a more preferred embodiment, the compounds of the presentinvention are represented by formula (Ia)

[0074] wherein;

[0075] X is O or NH and each of Z₁, Z₂, R₁, , Y and W are as definedabove.

[0076] More preferably, the compounds of the present invention arerepresented by formula (Ib)

[0077] wherein;

[0078] X is O or NH and each of Y and W are as defined above

[0079] Preferably, the [1,8] naphthyridine derivative is in the form ofthe (+) enantiomer, the (−) enantiomer or mixture of the (+) and (−)enantiomer including racemic mixture.

[0080] Preferably, the [1,8] naphthyridine derivative is in the form ofthe (+) enantiomer at least 95% free of the corresponding (−)enantiomer.

[0081] More Preferably, the [1,8] naphthyridine derivative is in theform of the (+) enantiomer at least 97% free of the corresponding (−)enantiomer.

[0082] Most Preferably, the [1,8] naphthyridine derivative is in theform of the (+) enantiomer at least 99% free of the corresponding (−)enantiomer.

[0083] Preferably, the [1,8] naphthyridine derivative is in the form ofthe (−) enantiomer at least 95% free of the corresponding (+)enantiomer.

[0084] More Preferably, the [1,8] naphthyridine derivative is in theform of the (−) enantiomer at least 97% free of the corresponding (+)enantiomer.

[0085] Preferably, the (1,8] naphthyridine derivative is in the form ofthe (−) enantiomer at least 99% free of the corresponding (+)enantiomer.

[0086] In one embodiment, the viral infection is chosen from Flavivirusinfections.

[0087] In one embodiment, the Flavivirus infection is chosen fromHepatitis C (HCV), bovine diarrhea(BVDV), hog cholera and yellow fever.

[0088] In an other embodiment, the Flavivirus infection is Hepatitis C.

[0089] In an other embodiment, the present invention also provides amethod for identifying compounds with anti-F1aviviral activity whichcomprises the step of screening the compounds in a BVDV assay andselecting compounds which show anti-BVDV activity.

[0090] In an other embodiment, the present invention also provides amethod for identifying compounds with anti-HCV activity which comprisesthe step of screening the compounds in a BVDV assay and selectingcompounds which show anti-BVDV activity.

[0091] Preferably the viral infection is hepatitis or herpes.

[0092] More preferably, the viral infection is HBV or HCV.

[0093] Most preferably the viral infection is HCV

[0094] Alternatively, the viral infection is HSV-1 or HSV-2.

[0095] In a preferred embodiment, the [1,8] naphthyridine derivative isselected from the group consisting of:

[0096] [1,8] naphthyridine-2-carboxylic acid 2-methoxybenzylamide

[0097] (Compound#1);

[0098] [1,8] naphthyridine-2-carboxylic acid benzylamide (Compound#2);

[0099] [1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamide(Compound#3);

[0100] [1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamide(Compound#4);

[0101] [1,8] naphthyridine-2-carboxylic acid2,4,6-trimethoxy-benzylamide (Compound#5);

[0102] [1,8] naphthyridine-2-carboxylic acid 2,3-dimethoxy-benzylamide(Compound#6);

[0103] [1,8] naphthyridine-2-carboxylic acid 2,4-dimethoxy-benzylamide(Compound#7);

[0104] [1,8] naphthyridine-2-carboxylic acid 2-isopropoxy-benzylamide(Compound #8);

[0105] (+)-[1,8] naphthyridine-2-carboxylic acid2-sec-butoxy-benzylamide (Compound #9);

[0106] (−) -1,8] naphthyridine-2-carboxylic acid2-sec-butoxy-benzylamide (Compound #10)

[0107] [1,8] naphthyridine-2-carboxylic acid[2-(2-methoxyphenyl)ethyl]-[amide (Compound #11)

[0108] [1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide(Compound#12);

[0109] [1,8] naphthyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide(Compound#13);

[0110] [1,8] naphthyridine-2-carboxylic acid pyridin-4-ylamide (Compound#14)

[0111] [1,8] naphthyridine-2-carboxylic acid pyridin-2-ylamide (Compound#15)

[0112] [1,8] naphthyridine-2-carboxylic acid 2-fluorobenzylamide(Compound #16)

[0113] [1,8] naphthyridine-2-carboxylic acid 2-chlorobenzylamide(Compound #17);

[0114] [1,8] naphthyridine-2-carboxylic acid2-trifluoromethoxy-benzylamide (Compound #18);

[0115] [1,8] naphthyridine-2-carboxylic acid (3-nitrophenyl)-amide(Compound #19);

[0116] N-(5,7-dimethyl-[1,8]naphthyridin-2-yl)-2-(2-methoxyphanyl)-acetamide (Compound #20);

[0117] [1,8] naphthyridine-2-carboxylic acid benzyloxyamide (Compound#21);

[0118] (1,8] naphthyridine-2-carboxylic acid thiazol-2-ylamide (Compound#22);

[0119] [1,8] naphthyridine-2-carboxylic acid benzothiazol-2-ylamide(Compound #23 );

[0120] [1,8] naphthyridine-2-carboxylic acid (2-fluoro-phenyl)-amide(Compound #24);

[0121] [1,8] naphthyridine-2-carboxylic acid(2-methoxy-benzyl)-methyl-amide (Compound #25):

[0122] [1,8] naphthyridine-2-carbothioic acid 2-methoxy-benzylamide(Compound #26);

[0123] (2-methoxy-benzyl)-(1,8]naphthyridine-2-carboxamidinetrifluoroacetate (Compound #27);

[0124] [1,8] naphthyridine-2-carboxylic acid phenyl-amide (Compound#28);

[0125] [1,8] naphthyridine-2-carboxylic acid pyridin-3-yl-amide(Compound #29);

[0126] [1,8] naphthyridine-2-carboxylic acid(phenyl-3-trifluoromethyl)-amide (Compound #30); and

[0127] 1,8] naphthyridine-2-carboxylic acid(phenylmethyl-3-trifluoromethyl)-amide (Compound #31).

[0128] More preferably, the [1,8] naphthyridine derivative is selectedfrom the group consisting of:

[0129] [1,8] naphthyridine-2-carboxylic acid 2-methoxybenzylamide(Compound #1);

[0130] [1,8] naphthyridine-2-carboxylic acid benzylamide (Compound #2);

[0131] [1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamide(Compound #3);

[0132] [1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamide(Compound #4);

[0133] [1,8] naphthyridine-2-carboxylic acid2,4,6-trimethoxy-benzylamide (Compound #5);

[0134] [1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide(Compound #12);

[0135] [1,8] naphthyridine-2-carboxylic acid 2-fluoro-benzylamide(Compound #16); and

[0136] [1,8] naphthyridine-2-carboxylic acid 2-chloro-benzylamide(Compound #17).

[0137] In accordance with the present invention there is provided acomposition useful as an antiviral agent, the composition comprising atleast one (1,8) naphthyridine derivative of Formula I, Ia, or Ib or apharmaceutically acceptable salt thereof in combination with apharmaceutically acceptable carrier.

[0138] Preferably, the antiviral activity of the composition of thepresent invention is anti-hepatitis or anti-herpes.

[0139] More preferably, the antiviral activity of the composition of thepresent invention is anti-hepatitis activity is anti-HBV or anti-HCV.

[0140] Most preferably, the antiviral activity of the composition of thepresent invention is anti-HCV.

[0141] Alternatively, the antiviral activity of the composition of thepresent invention is anti-HSV-1 or anti-HSV-2.

[0142] In accordance with the present invention, there is also provideda [1,8] naphthyridine derivative of Formula (I) (Ia) or (Ib) orpharmaceutically acceptable salts thereof; with the provisos that:

[0143] 1) when; Y is CH₂, X is O, R₁, Z₁, Z₁′, Z₁″ and Z₂ are H, and Ais

[0144] then W is not 2-methoxyphenyl or 3-trifluoromethylphenyl; and

[0145] 2)when; Y is (CH₂)₀, X is O, R₁, Z₁, Z₁′, Z₁″ and Z₂ are H, and Ais

[0146] then W is not phenyl, 3-trifluoromethylphenyl or 3-pyridinyl.

[0147] Compounds of the present invention can be synthesized usingconventional preparative steps and recovery methods known to thoseskilled in the art of organic chemistry. Examples of such syntheses areprovided in the experimental section.

[0148] The preferred general synthetic approach for the present [1,8]naphthyridine derivatives, as shown in the examples, comprises reacting[1,8] naphthyridine-2-carboxylic acid, which is commercially available,with a selected amino compound to form the [1,8] naphthyridinederivative of the present invention. Other modifications can be made tothe resulting molecule in accordance with well known procedures in thefield of organic synthesis.

[0149] Those skilled in the art will appreciate that certain compoundsof the present invention may contain one or more chiral centers and thusexists in the form of many different isomers, i.e., enantiomers,diastereoisomers and epimers. All such enantiomers, diastereoisomers andepimers are within the scope of the present invention, either in pureform or in admixture, including racemic mixtures.

[0150] Certain [1,8] naphthyridine derivatives of the present inventionform pharmaceutically acceptable salts. For example, compounds withbasic substituents such as an amino group form salts with weaker acids.Examples of suitable acids for salt formation include hydrochloric,sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic,fumaric, succinic, ascorbic, maleic, methanesulfonic, trifluoroaceticand other mineral and carboxylic acids well known to those skilled inthe art. The salts are prepared by contacting the free base form with asufficient amount of the desired acid to produce a salt in aconventional manner. The free base forms may be regenerated by treatingthe salt with a suitable diluted aqueous base solution such as diluteaqueous sodium hydroxide, potassium carbonate, ammonia and sodiumbicarbonate. The free base forms may differ from their respective saltforms somewhat in certain physical properties, such as solubility inpolar solvents, but the acid and base salts are otherwise equivalent totheir respective free base forms for purposes of the present invention.

[0151] The present invention is also concerned with a composition forinhibiting the hepatitis C virus. The composition comprises an effectiveamount of a compound of Formula I wherein A, W, X, Y, Z₁, Z₁′, Z₁″, Z₂,n, and R₁-R₃ are as defined above without the proviso, in associationwith a pharmaceutically acceptable carrier. Typically, they contain fromabout 0.1% to about 99% by weight of active compound, and preferablyfrom about 10% to about 60% by weight depending on which method ofadministration is employed. The compositions may be in the form oftablets, capsules, caplets, powders, granules, lozenges, suppositories,reconstitutable powders or liquid preparations such as oral or sterileparenteral solutions or suspensions. Conventional carriers includebinding agents such as acacia, gelatin, sorbitol, polyvinylpyrrolidone;fillers such as lactose, sugar, maize-starch, calcium phosphate,sorbitol or glycine; disintegrants such as starch, polyvinylpyrrolidone,sodium starch glycollate or microcrystalline cellulose; orpharmaceutically acceptable wetting agent such as sodium laurylsulphate.

[0152] The present compounds may be injected parenterally, i.e.,intramuscularly, intravenously, or subcutaneously. For parenteraladministration, the compound may be used in the form of sterilesolutions containing other solutes, for example, sufficient saline orglucose to make the solution isotonic.

[0153] The compounds may be administered orally in the form of tablets,capsules, or granules containing suitable conventional carriers orexcipients such as starch, lactose, white sugar etc. The compounds maybe administered orally in the form of solutions that may containcoloring and/or flavoring agents. The compounds may also be administeredsublingually in the form of tracheas or lozenges in which each activeingredient is mixed with sugar or corn syrups, flavoring agents anddyes, and then dehydrated sufficiently to make the mixture suitable forpressing into solid form. The amount of active ingredient administeredorally will depend on bioavailability of the specific compound.

[0154] The solid oral compositions may be prepared by conventionalmethods of blending, filling, tableting etc. Repeated blendingoperations may be used to distribute the active agent throughout thosecompositions employing large quantities of fillers. Such operations areconventional in the art. The tablets may be coated according to methodswell known in normal pharmaceutical practice, in particular with anenteric coating.

[0155] Oral liquid preparations may be in the form of emulsions, syrups,or elixirs, or may be presented as a dry product for reconstitution withwater or other suitable vehicle before use. Such liquid preparations mayor may not contain conventional additives. For example, suspendingagents, such as sorbitol, syrup, methyl cellulose, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, orhydrogenated edible fats; emulsifying agents, such as sorbitanmonooleate or acacia; non-aqueous vehicles (which may include edibleoils), such as almond oil, fractionated coconut oil, oily estersselected from the group consisting of glycerin, propylene glycol,ethylene glycol, and ethyl alcohol; preservatives, for instance methylpara-hydroxybenzoate, ethyl para-hydroxybenzoate, n-propylpara-hydroxybenzoate, or n-butyl para-hydroxybenzoate of sorbic acid;and, if desired, conventional flavoring or coloring agents.

[0156] For parenteral administration, fluid unit dosage forms may beprepared by utilizing the compound and a sterile vehicle, and, dependingon the concentration employed, may be either suspended or dissolved inthe vehicle. Once in solution, the compound may be injected and filtersterilized before filling a suitable vial or ampoule and subsequentlysealing the carrier or storage package. Adjuvants, such as a localanesthetic, a preservative or a buffering agent, may be dissolved in thevehicle prior to use. Stability of the pharmaceutical composition may beenhanced by freezing the composition after filling the vial and removingthe water under vacuum, (e.g., freeze-drying the composition).Parenteral suspensions may be prepared in substantially the same manner,except that the peptide should be suspended in the vehicle rather thanbeing dissolved, and, further, sterilization is not achievable byfiltration. The compound may be sterilized, however, by exposing it toethylene oxide before suspending it in the sterile vehicle. A surfactantor wetting solution may be advantageously included in the composition tofacilitate uniform distribution of the compound.

[0157] An inhibiting amount can be defined as the amount of activecompound required to slow the progression of viral replication or reduceviral load from that which would otherwise occur without administrationof the compound. Or, it is an amount of active compound required to slowthe progression or reduce the intensity of symptoms resulting fromhepatitis C virus or elimination thereof.

[0158] The compounds of the invention may also be used in combinationwith other antiviral agents.

[0159] In one embodiment, the compounds of the invention may be employedtogether with at least one other antiviral agent chosen from proteaseinhibitors, polymerase inhibitors, and helicase inhibitors.

[0160] In one embodiment, the compounds of the invention may be employedtogether with at least one other antiviral agent chosen from Interferonand Ribavirin.

[0161] In one embodiment, the compounds of the invention may be employedtogether with at least one other antiviral agent chosen fromInterferon-α and Ribavirin.

[0162] The combinations referred to above may conveniently be presentedfor use in the form of a pharmaceutical formulation and thuspharmaceutical formulations comprising a combination as defined abovetogether with a pharmaceutically acceptable carrier therefor comprise afurther aspect of the invention.

[0163] The individual components of such combinations may beadministered either sequentially or simultaneously in separate orcombined pharmaceutical formulations.

[0164] When the compound (I) or a pharmaceutically acceptable saltsthereof is used in combination with a second therapeutic agent activeagainst the same virus the dose of each compound may be either the sameas or differ from that when the compound is used alone. Appropriatedoses will be readily appreciated by those skilled in the art.

[0165] Physicians will determine the dosage of the present therapeuticagents that will be most suitable. Dosages may vary with the mode ofadministration and the particular compound chosen. In addition, thedosage may vary with the particular patient under treatment. The dosageof the compound used in the treatment will vary, depending on viralload, the weight of the patient, the relative efficacy of the compoundand the judgment of the treating physician. Such therapy may extend forseveral weeks or months, in an intermittent or uninterrupted manner.

[0166] The following examples are provided to illustrate various loembodiments of the present invention and shall not be consider aslimiting its scope.

EXAMPLE 1

[0167] [1,8] naphthyridine-2-carboxylic acid 2-methoxybenzylamide(Compound #1)

[0168] 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC)(132 mg, 0.69 mmol, 1.1eq.) was added to a solution of the acid 20 (111mg, 0.63 mmol), the amine (123 μL, 0.95 mmol, 1.5 eq.) andhydroxybenzotriazole (HOBT) (93 mg, 0.69 mmol, 1.1 eq.) in dry DMF (5mL) at room temperature. Reaction mixture was stirred at roomtemperature for 18 hours. It was then poured into brine, extracted withethyl acetate (3 times). Combined organic extracts 25 were washed withcitric acid 10%, sodium bicarbonate saturated solution, brine, driedover magnesium sulfate and concentrated to give a white solid (78%yield). When purification is needed, it was done by flash chromatographyusing ethylacetate as the eluent

[0169]¹H NMR (300 MHz; CDCl₃): 9.15 (m, 1H); 8.68 (bs, 1H); 8.45 (d, 1H,J=8.5 Hz); 8.34 (d, 1H, J=8.5 Hz); 8.25 (ad, 1H, J=1.9 and 8.2 Hz); 7.54(dd, 1H, J=4.4 and 8.1 Hz); 7.37 (dd, 1H, J=1.6 and 7.4 Hz); 7.27-7.22(m, 1H); 6.88 (m, 2H); 4.70 (d, 2H, J=6.3 Hz) and 3.86 (s, 3H) ppm.

[0170] Based on a method similar to that of example 1, the followingcompounds were prepared:

EXAMPLE 2

[0171] [1,8] naphthyridine-2-carboxylic acid benzylamide Compound #2

[0172]¹H NMR (300 MHz; CDCl₃): 9.15 (m, 1H); 8.70 (br.m, 1H) ; 8.49 (d,1H, J=8.2 Hz) ; 8.38 (d, 1H, J=8.4 Hz) ; 8.28 (m, 1H) ; 7.57 (m, 1H) ;7.30-7.10 (br. m, 5H) and 4.74 (d, 2H, J=6.1 Hz) ppm.

EXAMPLE 3

[0173] [1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamideCompound #3

[0174]¹H NMR (300 MHz; CDCl₃): 9.13 (m, 1H); 8.65 (bs, 1H); 8.44 (d, 1H,J=8.2 Hz); 8.35 (d, 1H, J=8.5 Hz); 8.25 (dd, 1H, J=1.9 and 8.2 Hz); 7.54(dd, 1H, J=4.1 and 8.1 Hz); 7.29 (d, 2H, J=8.5 Hz); 6.83 (d, 2H, J=8.5Hz); 4.61 (d, 2H, J=6 Hz) and 3.75(s, 3H) ppm.

EXAMPLE 4

[0175] [1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamideCompound #4

[0176]¹H NMR (400 MHz; CDCl₃): 9.10 (dd, 1H, J=1.9 and 4.1 Hz); 8.66(bs, 1H); 8.41 (d, 1H, J=8.3 Hz); 8.32 (d, 1H, J=8.3 Hz) 8.22 (dd, 1H,J=1.9 and 8.1 Hz); 7.52 (dd, 1H, J=4,2 and 8.2 Hz); 7.18 (t, 1H, J=8.0Hz); 6.90 (d, 1H, J=7.6 Hz); 6.85 (d, 1H, J=1.9 Hz); 6.75 (dd, 1H, J=2.4and 8.2 Hz); 4.61 (d, 2H, J=6.1 Hz) and 3.72 (s, 3H) ppm.

EXAMPLE 5

[0177] [1,8] naphthyridine-2-carboxylic acid2,4,6-trimethoxy-benzylamide Compound #5

[0178]¹H NMR (300 MHz; CDCl₃): 9.14 (dd, 1H, J=1.9 and 4.1 Hz); 8.49 (d,1H, J=8.2 Hz); 8.36-8.33(m, 2H); 8.26 (dd, 1H, J=1.9 and 8.2 Hz); 7.54(dd, 1H, J=4.1 and 8.2 Hz); 6.13 (s, 2H); 4.71 (d, 2H, J=5.2 Hz) and3.82 (s, 9H) ppm.

EXAMPLE 6

[0179] [1,8) naphthyridine-2-carboxylic acid 2,3-dimethoxy-benzylamideCompound #6

[0180]¹H NMR (300 MHz; CDCl₃): 9.14 (dd, 1H, J=1.9 and 4.3 Hz); 8.67(bs, 1H); 8.44 (d, 1H, J=8.2 Hz); 8.35 (6, 1H, J=8.5 Hz); 8.25 (dd, 1H,J=1.9 and 8.1 Hz); 7.54 (dd, 1H, J=4.1 and 8.2 Hz); 7.03-6.97 (m, 2H);6.86-6.83 (m, 1H); 4.73 (d, 2H, J=6 Hz); 3.89 (s, 3H) and 3.84 (s, 3H)ppm.

EXAMPLE 7

[0181] [1,8] naphthyridine-2-carboxylic acid 2,4-dimethoxy-benzylamideCompound #7

[0182]¹H NMR (300 MHz; CDCl₃): 9.12 (bs, 1H); 8.60 (bs, 1H); 8.41 (d,1H, J=8.2 Hz); 8.31 (d, 1H, J=8.5 Hz); 8.22 (dd, 1H, J=1.9 and 8.2 Hz);7.52 (dd, 1H, J=4.1 and 8.2 Hz); 7.27 (d, 1H, J=6 Hz); 6.42-6.38 (m,2H); 4.60 (d, 2H, J=6 Hz); 3.81 (s, 3H) and 3.75 (s, 3H) ppm.

EXAMPLE 8

[0183] [1,8] naphthyridine-2-carboxylic acid 2-isopropoxy-benzylamideCompound #8

[0184]¹H NMR (300 MHz; CDCl₃): 9.17 (m, 1H); 8.72 (br. M, 1H); 8.49 (d,1H, J=8.5 Hz); 8.38 (d, 1H, J=8.2 Hz); 8.27 (m, 1H); 7.57 (dd, 1H, J=4.1and 9.1 Hz); 7.35 (m, 1H); 7.30-7.20 (m, 1H, mixed with CDCl₃); 6.88 (m,2H); 4.72 (d, 2H, J=6 Hz); 4.62 (m, 1H); 1.40 (s, 3H) and 1.38 (s, 3H)ppm.

EXAMPLE 9

[0185] (+)-[1,8] naphthyridine-2-carboxylic acid2-sec-butoxy-benzylamide Compound #9

[0186] α_(D): +17.1° (MeOH, 22.7 mM, room temp.)

[0187]¹H NMR (300 MHz; CDCl₃): 9.17 (m, 1H); 8.69 (br. m, 1H); 8.48 (d,1H, J=8.2 Hz); 8.38 (d, 1H, J=8.5 Hz); 8.28 (dd, 1H, J=1.9 and 8.2 Hz);7.58 (m, 1H); 7.36 (d, 1H, J=7.7 Hz); 7.23 (d, 1H, under CDCl₁); 6.88(m, 2H); 4.73 (d, 2H, J=6.0 Hz) 4.40 (m, 1H); 1.77 (m, 2H); 1.33 (d, 3H,J=6.1 Hz) and 0.97 (t, 3H, J=7.4 Hz) ppm.

EXAMPLE 10

[0188] (−)-1,8] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamideCompound #10

[0189] α_(D): −21.1° (MeOH, 24.6 mM, room temp.)

[0190]¹ NMR (300 MHz; CDCl₃): 9.13 (m, 1H), 8.68 (br. m, 1H); 8.44 (d,1H, J=8.5 Hz); 8.33 (d, 1H, J=8.5 Hz); 8.23 (dd, 1H, J=1.9 and 8.2 Hz)7.52 (m, 1H); 7.35 (m, 1H); 7.20 (m, 1H); 6.86 (m, 2H); 4.71 (d, 2H,J=6.0 Hz); 4.37 (m, 1H); 1.72 (m, 2H) 1.30 (d, 3H, J=6.0 Hz) and 0.95(t, 3H, J=7.4 Hz) ppm.

EXAMPLE 11

[0191] [1,8) naphthyridine-2-carboxylic acid[2-(2-methoxy-phenyl)-ethyl]-amide Compound #11

[0192] 1H NMR (300 MHz; CDCl₃): 9.14 (bs, 1H); 8.60 (m, 1H); 8.42 (d,1H, J=8.2 Hz); 8.34 (d, 1H, J=8.5 Hz); 8.24 (dd, 1H, J=1.9 and 8.2 Hz);7.54 (dd, 1H, J=4.1 and 8.2 Hz); 7.16 (d, 2H, J=7.1 Hz); 6.83 (d, 2H,J=7.7 Hz); 3.86 (s, 3H) and 2.98 (m, 2H) ppm.

EXAMPLE 12

[0193] [1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amideCompound #12

[0194]¹H NMR (300 MHz; CDCl₃): 9.13-9.12 (m, 1H); 8.79 (bs, 1H); 8.62(bs, 1H); 8.49 (bs 1H); 8.39 (dd, 2H, J=8.2 and 15 Hz); 8.25 (dd, 1H,J=1.9 and 8.2 Hz); 7.70-7.69 (m, 1H); 7.54 (dd, 1H, J=4.4 and 8.2 Hz);7.26-7.20 (m, 1H) and 4.68 (d, 2H, J=6.3 Hz) ppm.

EXAMPLE 13

[0195] [1,8] naphthyridine-2-carboxylic acid (pyridin-2-ylmethyl)-aimideCompound #13

[0196]¹H NMR (300 MHz; CDCl₃): 9.21 (dd, 1H, J=1.9 and 4.2 Hz); 9.12(bs, 1H); 8.61 (d, 1H, J=4.9 Hz); 8.49 (d, 1H, J=8.2 Hz); 8.41 (d, 1H,J=8.5 Hz); 8.30 (dd, 1, J=1.9 and 8.2 Hz); 7.70-7.64 (m, 2H); 7.60 (dd,1H, J=4.1 and 8.1 Hz); 7.38 (d, 1H, J=7.7 Hz); 7.26-7.20 (m, 1H) and4.88 (d, 2H, J=6 Hz) ppm.

EXAMPLE 14

[0197] [1,8] naphthyridine-2-carboxylic acid pyridin-4-ylamide Compound#14

[0198]¹H NMR (300 MHz; CDCl₃): 10.45 (bs, 1H); 9.27 (dd, 1H, J=1.9 and4.3 Hz); 8.65 (bs, 1H); 8.52 (dd, 2H, J=8.5 and 15 Hz); 8.36 (dd, 1H,J=1.9 and 8.2 Hz); 7.86 (m, 2H); 7.68 (dd, 1H, J=4.1 and 8.2 Hz) and7.27-7.26 (m, 1H) ppm.

EXAMPLE 15

[0199] [1,8] naphthyridine-2-carboxylic acid pyridin-2-ylamide Compound#15

[0200]¹H NMR (300 MHz; CDCl₃): 10.77 (bs, 1H); 9.23 (bs, 1H), 8.52-8.28(m, 5H); 7.79-7.74 (m, 1H); 7.63-7.59 (m, 1H) and 7.10-7.06 (m, 1H) ppm.

EXAMPLE 16

[0201] [1,8] naphthyridine-2-carboxylic acid 2-fluoro-benzylamideCompound #16

[0202]¹H NMR (300 MHz; CDCl₃): 9.14 (bs, 1H); 8.69 (m, 1H); 8.43 (d, 1H,J=8.5 Hz); 8.35 (d, 1H, J=8,5 Hz); 8.25 (dd, 1H, L=1.9 and 8 Hz); 7.55(dd, 1H, J=4.1 and 8.1 Hz); 7.44-7.38 (m, 1H); 7.27-7.19 (m, 1H);7.10-6.99 (m, 2H) and 4.74 (d, 2H, J=6 Hz) ppm.

EXAMPLE 17

[0203] [1,8] naphthyridine-2-carboxylic acid 2-chloro-benzylamideCompound #17

[0204]¹H NMR (300 MHz; CDCl₃): 9.13 (d, 1H, J=1.9 HZ); 8,73 (bs, 1H);8.42 (d, 1H, J=8.5 Hz); 8.33 (d, 1H, J=8.5 Hz); 8.23 (dd, 1H, J=1.9 and8.3 Hz); 7.53 (dd, 1H, J=4.1 and 8.2 Hz); 7.45-7.42 (m, 1H); 7.35-7.32(m, 1H); 7.21-7.17 (m, 1H) and 4.77 (d, 2H, J=6 Hz) ppm.

EXAMPLE 18

[0205] [1,8] naphthyridine-2-carboxylic acid2-trifluoromethoxy-benzylamide Compound #18

[0206]¹H NMR (300 MHz; CDCl₃): 9.16 (d, 1H, J=2.5 Hz); 8.7 (bs, 1H);8.46 (d, 1H, J=8.2 Hz); 8.38 (d, 1H, J=8.5 Hz); 8.27 (dd, 1H, J=1.9 and8.1 Hz); 7.57 (dd, 1H, J=4.1 and 8.2 Hz); 7.51-7.21 (m, 2H) and 4.78 (d,2H, J=6 Hz) ppm.

EXAMPLE 19

[0207] [1,8] naphthyridine-2-carboxylic acid (3-nitrophenyl)-amideCompound #19

[0208]¹H NMR (300 MHz; CDCl₃): 9.25 (dd, 1H, J=1.9 and 4.1 Hz); 9.04 (t,1H, J=1.9 Hz); 8.76 (d, 1H, J=8.5 Hz); 8.63 (dd, 1H, J=1.9 and 8.2 Hz);8.40-8.35 (m, 2H); 8.02-7.99 (m, 1H); 7.79 (dd, 1H, J=4.1 and 8 Hz) and7.69 (t, 1H, J=8.2 Hz) ppm.

EXAMPLE 20

[0209] N-(5,7-dimethyl-[1,8]naphthyridin-2-yl)-2-(2-methoxyphenyl)-acetamide Compound #20

[0210]¹H NMR (300 MHz; CDCl₃): 8.48 (d, 1H, J=8.8 Hz); 8.40 (bs, 1H);

[0211] 8.27 (d, 1H, J=9 Hz); 7.35-7.28 (m, 2H); 7.08 (d, 1H, J=0.6 Hz);7.00-6.93 (m, 2H); 3.90 (s, 3H); 3.80 (s, 2H); 2.66 (s, 3H) and 2.62 (s,3H) ppm.

EXAMPLE 21

[0212] [1,8] naphthyridine-2-carboxylic acid benzyloxyamide Compound #21

[0213]¹H NMR (300 MHz; CDCl₃): 10.53 (bs, 1H); 9.18 (bs, 1H); 8.42 (m,2H); 8.29 (d, 1H, J=7.1 Hz); 7.60 (m, 1H); 7.47-7.26 (m, 6H) and 5.1 (s,2H) ppm.

EXAMPLE 22

[0214] [1,8] naphthyridine-2-carboxylic acid thiazol-2-ylamide Compound#22

[0215]¹H NMR (400 MHz; CDCl₃) 11.50 (bs, 1H); 9.25 (dd, 1H, J=1.8 and4.1 Hz); 8.49 (dd, 2H, J=8.3 and 14 Hz); 8.33 (dd, 1H, J=1.8 and 8.2Hz); 7.64 (dd, 1H, J=4.1 and 8.2 Hz); 7.58 (d, 1H, 3.5 Hz) and 7.07 (d,1H, J=3.5 Hz) ppm.

EXAMPLE 23

[0216] [1,8] naphthyridine-2-carboxylic acid benzothiazol-2-ylamideCompound #23

[0217]¹H NMR (300 MHz; CDCl₃): 9.28 (d, 1H, J=4.1 Hz); 8.55-8.48 (m,2H); 8.36-8.32 (m, 1H); 7.87 (d, 2H, J=8 Hz); 7.69-7.63 (m, 1H);7.50-7.45 (m, 1H); 7.37-7.34 (m, 1H) and 7.32-7.26 (m, 1H) ppm.

EXAMPLE 24

[0218] [1,8] naphthyridine-2-carboxylic acid (2-fluoro-phenyl)-amideCompound #24

[0219]¹H NMR (300 MHz: CDCl₃): 10.4 (bs, 1H); 9.20 (dd, 1H, J=1.9 and4.1 Hz); 8.51-8.39 (m, 3H); 8.27 (dd, 1H, J=1.8 8.2 Hz); 7.57 (dd, 1H.J=4.2 and 8.2) and 7.19-7.07 (m, 3H) ppm.

EXAMPLE 25

[0220] [1,8] naphthyridine-2-carboxylic acid(2-methoxy-benzyl)-methyl-amide Compound #25

[0221] To a suspension of sodium hydride (10 mg) in DMF (1 mL) at 0° C.was added a solution of the compound of Example 1 (68 mg, 0.23 mmol) inDMF (1 mL). The reaction mixture was stirred at the same temperature for30 minutes then methyl iodide (20 μL, 0.32 mmol) was added. Reactionmixture was stirred at room temperature overnight. It was then pouredinto ethyl acetate, washed with water, brine, dried over magnesiumsulfate and concentrated to give a white solid. Purification was doneusing a silica gel column and ethyl acetate as the eluent.

[0222] 1H NMR (300 MHz; CDCl₃): Mixture of rotamers 9.13 (m, 1H);8.29-8.18 (m, 2H); 7.86 (dd, 1H, J=8.2 and 12 Hz); 7.58-7.11 (complexmixture ; 3H); 6.98-6.71 (complex mixture, 2H); 4.91 and 4.85 (2s, 2H)and 3.84 and 3.58 (2s, 3H); 3.18 and 3.04 (2s, 3H) ppm.

EXAMPLE 26

[0223] [1,8] naphthyridine-2-carbothioic acid 2-methoxy-benzylamideCompound #26

[0224] Lawesson's reagent (52 mg 0.13 mmol, 0.5 eq.) was added to asolution of the amide (75.3 mg, 0.26 mmol) in benzene (5 mL) and thesolution was refluxed during 2 hours. Solvent was evaporated and theyellow solid was purified by flash chromatography using ethylacetate/hexane 50% to give a yellow solid, which was precipitated withether (62% yield).

[0225]¹H NMR (300 MHz; CDCl₃): 10.64 (bs, 1H); 9.15 (dd, 1H, J=1.9 and4.1); 9.02 (d, 1H, J=8.5 Hz); 8.32 (d, 1H, J=8.5 Hz); 8.26 (dd, 1H,J=1.9 and 8.1 Hz); 7.56 (dd, 1H, J=4.1 and 8.2 Hz); 7.40 (dd, 1H, J=1.1and 7.4 Hz); 7.33-7.26 (m, 1H); 6.95-6.90 (m, 2H); 5.10 (d, 2H, J=5.5Hz) and 3.88 (s, 3H) ppm.

EXAMPLE 27

[0226] N-(2-methoxy-benzyl)-[1,8]naphthyridine-2-carboxamidinetrifluoroacetate Compound #27

[0227] Ammonia was bubbled into a solution of the ester (144 mg, 0.76mmol) in methanol (10 mL) at 0° C., until saturation of the solution.Then solution was closed and stirred at room temperature overnight.Reaction mixture was flushed with nitrogen and concentrated to give awhite solid (100% yield).

[0228]¹H NMR (300 MHz; CDCl₃): 9.17 (bs, 1H); 8.62 (d, 1H, J=8.2 Hz);8.55 (dd, 1H, J=1.6 and 8.2 Hz): 8.35 (d, 1H, J=8.2 Hz); 7.74 (dd, 1H,J=4.3 and 8.2 Hz) and 4.87 (s, 2H) ppm.

[0229] Thionyl chloride (78 μL, 1.06 mmol, 1.4 eq.) was added to asolution of the amide (132 mg, 0.76 mmol) and NMM (0.24 mL, 2.128 mmol,2.8 eq.) in DMF (8 mL) at 0° C. Reaction mixture was stirred at the sametemperature for 30 minutes then at room temperature for 2 hours then itwas poured into ice-cold water and extracted with ethyl acetate (3×).Combined extracts were washed with citric acid 10%, sodium bicarbonatesaturated solution, brine, dried over magnesium sulfate and concentratedto give a green solid. Product was purified by flash chromatographyusing ethyl acetate to give a white solid (25% yield).

[0230]¹H NMR (300 MHz; CDCl₃): 9.28 (dd; 1H, J=1.9 and 4.1 Hz); 8.42 (d,1H, J=8.2 Hz); 8.32 (dd, 1H, J=1.9 and 8.2 Hz); 7.83 (d, 1H, J=8.2 Hz)and 7.66 (dd, 1H, J=4.1 and 8.3 Hz) ppm,

[0231] HCl gas was bubbled into a solution of the cyano compound (30 mg,0.19 mmol) in ethanol (5 mL) at 0° C. (10 minutes) Reaction mixture wascapped and put in the refrigerator for 18 hours. Then nitrogen wasbubbled into the solution and the reaction mixture was concentrated. Theresidue was put into DMF (2 mL) and treated with triethylamine (26 μL,0.19 mmol, 1 eq.) and the amine (50 μL, 0.38 mmol, 2 eq.). Reactionmixture was stirred at 60° C. overnight. After cooling, the reactionmixture was partitioned between ethyl acetate and water, Organic layerwas washed with water, brine, dried and concentrated to give a yellowoil.

[0232] Purification by flash chromatography using EtOAc/MeOH/NH₄OH98/1/1 followed by an HPLC purification gave a white solid (98.6% pure)(25% yield).

[0233]¹H NMR (300 MHz; CDCl₃): 9.14 (dd, 1H, J=1.9 and 4.4 Hz); 8.64 (d,1H, J=8.5 Hz); 8.29-8.24 (m, 2H); 7.54 (dd, 1H, J=4.4 and 8 Hz);7.29-7.21 (m, 1H); 6.98-6.89 (m, 2H); 4.56 (s, 2H); 3.83 (s, 3H): 3.84(S. 1H) and 3.74 (s, 1H) ppm.

[0234] The following compounds were purchased at Peakdale:

[0235] [1,8] naphthyridine-2-carboxylic acid phenyl-amide Compound #28(PFC 023)

[0236] [1,8] naphthyridine-2-carboxylic acid pyridin-3-yl-amide Compound#29 (PFC-024)

[0237] [1,8] naphthyridine-2-carbcxylic acid(phenyl-3-trifluoromethyl)-amide Compound #30 (PFC-025)

[0238] [1,8] naphthyridine-2-carboxylic acid(phenylmethyl-3-trifluorompthyl)-anide Compound #31 (PFC-026)

TABLE 1 COMPOUNDS OF THE PRESENT INVENTION compound# Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

EXAMPLE 28

[0239] ANTIVIRAL ACTIVITY

[0240] BVDV anti-viral Assay

[0241] Currently, the WST-1 based BVDV assay, is being used as surrogateto evaluate potential anti-HCV agents since BVDV (bovine viral diarrheavirus) shares functional homology with the HCV.

[0242] WST-1 based BVDV anti-viral assay

[0243] To determine the anti-viral effect of the compounds, MDBK cellswere infected with the cytopathic strain of BVDV(NADL) using a 0.006 to0.01 MOI. 3000 cells were then seeded in each well of a 96-well platecontaining the compound. The final volume was 200 μl of media per wells.Following 4 days incubation at 37° C., medium was removed and 100 μl ofWST-1 (diluted {fraction (1/40)}) in culture media was added to wells.Cell culture was then incubated for another 2 hrs at 37° C., after which20 μl of 10% SDS was added to each well in order to inactivate the virusand the OD at 450 nm was determined using a microplate reader (DynatechMR5000).

[0244] In parallel, the same experiment was performed using non-infectedcells to determine the compound toxicity. The percentage of cytopathiceffect (CPE) reduction and the percentage of viable cells is calculatedusing these data. The results appear in Table 2 below. TABLE 2 BVDVantiviral Toxicity effect WST-1 compound # IC₅₀ (μM) CC₅₀ (μM) 1˜6.8 >68.2 2 <76 >76 3 ˜1.7 >68.2 4 ˜6.8 >68.2 5 ˜1.1 >56.6 8<62.2 >62.2 10 >6 >6 12 ˜18.9 >75.7 13 >7.6 >75.7 <75.7 15 >8 >79.9<79.9 16 ˜1.1 >71.1 17 ˜3.6 >67.2 19 ˜1.7 >68 22 >0.78 >78 <7.823 >0.65 >6.5 <6.5 24 ˜7.5 >74.8 27 ˜0.33 >63.2 28 >8 >80.2 <80 29˜3.2 >79.9 (HCl salt) 30 ˜0.6 6.3 31 ˜3 >60.4

[0245] HERPES SIMPLEX VIRUS PLAQUE REDUCTION ASSAY

[0246] Confluent monolayers of Vero cells in 24-well tissue culturedishes were inoculated with 300 μl of HSV-1 (300 pfu/ml) (KOS) or HSV-2(300 pfu/ml) (186) diluted in PMEM medium. After adsorption at 37° C.for one hour the monolayers were overlaid with medium containing testcompound at several concentrations. Infected but otherwise untreatedmonolayers were included in the assay as virus controls. Afterincubation at 37° C. in 5% CO₂/air post-infection for 48 hours, theplates were fixed and stained with crystal violet 2%/EtOH 20% for a fewseconds. The monolayers were examined for the presence of plaques undera microscope. The percentage plaque reduction was determined for eachcompound and the 50% inhibitory concentration (IC₅₀) established.

[0247] The CC₅₀ value (cell cytotoxicity dose at 50%) was assessed onvirus-free control layers of cells to assess the toxicity of thecompounds.

[0248] Inhibition of Human Hepatitis B virus.

[0249] The method used for this test is described in detail in Korba etal., Antiviral Research 15, 217-228 (1992) which is shortly described asfollows:

[0250] Hep G2 cells transfected with human hepatitis B virus genomic DNA(2.2.15 cells) were grown and maintained in RPMI-1640 culture mediumcontaining %5 foetal bovine serum, 2mM glutamine and 50 μg/ml gentamicinsulphate, and checked routinely for G418 resistance. Cultures of 2.2.15cells were grown to confluence in 24 well tissue culture plates andmaintained for 2 to 3 days in that condition prior to drug treatment.

[0251] Drugs were dissolved in sterile water or sterile 50% DMSO inwater at concentrations 100-fold higher than the higher testconcentration. These solutions were diluted as needed in culture medium.

[0252] The culture medium on the confluent cells was changed 24 hoursprior to exposure to test compounds. During the 10 day treatment, theculture medium was changed daily. After 10 days of the treatment, theculture medium was collected and frozen at −70° C. for HBV DNA analysis.

[0253] To analyse extracellular HBV DNA, 0.2ml samples of culture mediumwere incubated for 20 minutes at 25° C. in 1M NaOH/10X SSC (1×SSC is0.15M NaCl/0.015M Sodium Citrate, pH 7.2) and then applied tonitrocellulose membranes presoaked in 20×SSC. Filters were then rinsedin 2×SSC and baked at 80° C. for 1 hour under vacuum,

[0254] A purified 3.2 kb EcoR1 BV DNA fragment was labelled with[³²]PdCTP by nick translation and used as a probe to detect HBV DNA onthe dot-blot by DNA hybridisation. After washing, the hybridised blotwas dried and ³²P was quantified using an Ambis beta scanner.

[0255] While the invention has been described in connection withspecific embodiments thereof, it will be understood that it is capableof further modifications and this application is intended to cover anyvariations, uses or adaptations of the invention following, in general,the principles of the invention and including such departures from thepresent description as come within known or customary practice withinthe art to which the invention pertains, and as may be applied to theessential features hereinbefore set forth, and as follows in the scopeof the appended claims.

What is claimed is:
 1. A method for the inhibition of a viral infection in a mammal, the method comprising administering to the mammal an antiviral amount of a [1,8] naphthyridine derivative of Formula I or a pharmaceutically acceptable salt thereof;

wherein Z₁, Z₁′, Z₁″ and Z₂ are independently H, halogen, carboxyl, amino, amidino, guanidino, nitro, OR, SH, CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy or C₁₋₆ heteroalkyl; A is

X is O, NH or S; Y is O, S, (CH₂)_(n), O(CH₂)_(n), or S(CH₂)_(n); with n is 0 to 6; R₁ and R₂ are independently H or C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl; or R₁ and R₂ together form a saturated or unsaturated 5 or 6 member heterocycle; W is C₆₋₁₂ aryl, C₆₋₁₂ heteroaryl, or C₃₋₁₂ heterocycle
 2. The method of claim 1 wherein Z₁, Z₁′, Z₁″ and Z₂ are independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl which can be s substituted with one or more halogen, OH, carboxy, amino, guanidino, amidino, nitro, SH or CN.
 3. The method of claim 1 wherein wherein R₁ and R₂ are independently C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkynyl which is substituted by one or more C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylthio, halogen, amino, guanidino, amidino nitro, OH, SH or CN.
 4. The method of claim 1 wherein wherein R₁ and R₂ together form a saturated or unsaturated 5 or 6 member heterocycle substituted with one or more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₅ alkynyl, C₁₋₅ alkoxy or C₁₋₆heteroalkyl, halogen, amino, guanidino, amidino, nitro, OH, SH or CN.
 5. The method of claim 1 wherein wherein W is C₆₋₁₂ aryl, C₆₋₁₂ heteroaryl, C₃₋₁₂ heterocycle, either of which is substituted with one or more C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₂₋₆ perfluoroalkyl, C₁₋₆ alkoxy, C₁₋₆ perfluoroalkoxy, C₁₋₆ heteroalkyl, C₁₋₆ perfluoroalkylthio, halogen, amino, guanidino, amidino, nitro, OH, COOH, SH or CN.
 6. The method of claim 1 wherein wherein Y is (CH₂)_(n) and wherein n is chosen between 0 to
 6. 7. The method of claim 1 wherein X is O.
 8. The method of claim 1 wherein X is S.
 9. The method of claim 1 wherein X is NH.
 10. The method of claim 1 wherein R is H.
 11. The method of claim 1 wherein Z₁, Z₁′ and Z₁″ are H
 12. The method of claim 1 wherein Z₂ is H.
 13. The method of claim 1 wherein Z₁, Z₁′, Z₁″ and Z₂ are H.
 14. The method of claim 1 wherein R₁, Z₁, Z₁′, Z₁″ and Z₂ are H.
 15. The method of claim 1 wherein R₁, Z₁, Z₁′, Z₁″ and Z₂ are H and Y is (CH₂)_(n) wherein n is chosen between 0 to
 6. 16. The method of claim 1 wherein n is
 0. 17. The method of claim 1 wherein A is


18. The method of claim 1 wherein A is


19. The method of claim 1 wherein A is


20. The method of claim 17 wherein W is phenyl or pyridinyl unsubstituted or substituted with one or more C₁₋₆ alkoxy group,
 21. The method of claim 17 wherein R₁, is H, Z₁, Z₁′, Z₁″ are is H and Z₂ is H.
 22. The method of claim 17 wherein Y is (CH₂)_(n) and n is
 0. 23. The method of claim 17 wherein Y is (CH₂)_(n) and n is
 1. 24. The method of claim 17 wherein Y is (CH₂)_(n) and n is
 2. 25. The method of claim 17 wherein X is S, R₁ is H, Z₁, Z₁′, Z₁″ are H is and Z₂ is H.
 26. The method of claim 17 wherein X is O, R₁ is H, Z₁, Z₁′, Z₁″ are H and Z₂ is H.
 27. The method of claim 17 wherein X is NH, R₁ is H, Z₁, Z₁′, Z₁″ are H and Z₂ is H.
 28. The method according to any one of claims 1 to 27 wherein said naphthyridine derivative is in the form of the (+) enantiomer, the (−) enantiomer or mixture of the (+) and (−) enantiomer including racemic mixture.
 29. The method according to any one of claims 1 to 27 wherein the viral infection is hepatitis or herpes.
 30. The method according to any one of claims 1 to 27 wherein the viral infection is HEV or HCV.
 31. The method according to any one of claims 1 to 27, wherein the viral infection is HCV
 32. The method according to any one of claims 1 to 27, wherein the viral infection is HSV-1 or HSV-2.
 33. The method according to claim 28 wherein the viral infection is HCV
 34. A method for the inhibition of a viral infection in a mammal, the method comprising administering to the mammal an antiviral amount of a [1,8] naphthyridine derivative selected from the group consisting of: [1,8] naphthyridine-2-carboxylic acid 2-methoxybenzylamide (Compound #1); [1,8] naphthyridine-2-carboxylic acid benzylamide (Compound #2); [1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamide (Compound #3); [1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamide (Compound #4); [1,8] naphthyridine-2-carboxylic acid 2,4,6-trimethoxy-benzylamide (Compound #5); (1,8] naphthyridine-2-carboxylic acid 2,3-dimethoxy-benzylamide (Compound #6); [1,8] naphthyridine-2-carboxylic acid 2,4-dimethoxy-benzylamide (Compound #7); [1,8] naphthyridine-2-carboxylic acid 2-isopropoxy-benzylamide (Compound #8); [1,8] naphthyridine-2-carboxylic acid [2-(2-methoxyphenyl)ethyl]-amide (Compound #11); [1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide (Compound #12); [1,8] naphthyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide (Compound #13), [1,8) naphthyridine-2-carboxylic acid pyridin-4-ylamide (Compound #14); [1,8] naphthyridine-2-carboxylic acid pyridin-2-ylamide (Compound #15); [1,8] naphthyridine-2-carboxylic acid 2-fluoro-benzylamide (Compound #16); [1,8] naphthyridine-2-carboxylic acid 2-chloro-benzylamide (Compound #17); [1,8] naphthyridine-2-carboxylic acid 2-trifluoromethoxy-benzylamide (Compound #18); [1,8] naphthyridine-2-carboxylic acid (3-nitrophenyl)-amide (Compound #19); N-(5,7-dimethyl-[1,8] naphthyridin-2-yl)-2-(2-methoxyphenyl)-acetamide (Compound #20); [1,8] naphthyridine-2-carboxylic acid benzyloxyamide (Compound #21); [1,8] naphthyridine-2-carboxylic acid thiazol-2-ylamide (Compound #2) [1,8] naphthyridine-2-carboxylic acid benzothiazol-2-ylamide (Compound #23); [1,8] naphthyridine-2-carboxylic acid (2-fluoro-phenyl)-amide (Compound #24); [1,8] naphthyridine-2-carboxylic acid (2-methoxy-benzyl)-methyl-amide (Compound #25); [1,8] naphthyridine-2-carbothioic acid 2-methoxy-benzylamide (Compound #26); (2-methoxy-benzyl)-[1,8]naphthyridine-2-carboxamidine trifluoroacetate (Compound #27); [1,8] naphthyridine-2-carboxylic acid phenyl-amide(Compound #28); [1,8] naphthyridine-2-carboxylic acid pyridin-3-yl-amide (Compound 29); [1,8] naphthyridine-2-carboxylic acid (phenyl-3-trifluoromethyl)-amide (Compound #30);and 1,8] naphthyridine-2-carboxylic acid (phenylmethyl-3-trifluoromethyl)-amide (Compound #31).
 35. The method according to claim 34 wherein said naphthyridine derivative is in the form of the (+) enantiomer, the (−) enantiomer or mixture of the (+) and (−) enantiomer including racemic mixture.
 36. A method for the inhibition of a viral infection in a mammal, the method comprising administering to the mammal an antiviral amount of a [1,8] naphthyridine derivative selected from the group consisting of (+)-[1,8] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamide (Compound 99); and (−)-[1,8] naphthyridine-2-carboxylic acid 2-sec-butoxy benzylamide (Compound #10).
 37. The method of claim 34 wherein said [1,8] naphthyridine derivative is selected from the group consisting of: [1,8] naphthyridine-2-carboxylic acid 2-methoxybenzylamide (Compound #1); [1,8] naphthyridine-2-carboxylic acid benzylamide (Compound #2); [1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamide (Compound #3); [1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamide (Compound #4); [1,8] naphthyridine-2-carboxylic acid 2,4,6-trimethoxy-benzylamide (Compound #5); [1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide (Compound #12); [1,8] naphthyridine-2-carboxylic acid 2-fluoro-benzylamide (Compound #16); [1,8] naphthyridine-2-carboxylic acid 2-chloro-benzylamide (Compound #17); and (2-methoxy-benzyl)-[I,8]naphthyridine-2 -carboxamidine trifluoroacetate(Compound #27).
 38. The method according to claim 37 wherein said naphthyridine derivative is in the form of the (+) enantiomer, the (−) enantiomer or mixture of the (+) and (−) enantiomer including racemic mixture.
 39. The method according to any one of claims 34 to 38 wherein the viral infection is hepatitis or herpes.
 40. The method according to any one of claims 34 to 38 wherein the viral infection is HBV or HCV.
 41. The method according to any one of claims 34 to 38, wherein the viral infection is HCV
 42. The method according to any one of claims 34 to 38, wherein the viral infection is HSV-1 or HSV-2.
 43. A composition useful as an antiviral agent, the composition comprising at least one [1,8] naphthyridine derivative of Formula I or a pharmaceutically acceptable salt thereof;

wherein A, Z₁, Z₁′, Z₁″ and Z₂ are as defined in any one of claims 1 to 27 and 34 to
 38. 44. A composition useful as an antiviral agent, the composition comprising at least one [1,8] naphthyridine derivative of Formula I or a pharmaceutically acceptable salt thereof;

wherein A, Z₁, Z₁′, Z₁″ and Z₂ are as defined in claim
 28. 45. The composition according to claim 44, wherein the antiviral activity is anti-hepatitis or anti-herpes.
 46. The composition according to claim 44, wherein said is anti-hepatitis activity is anti-HBV or anti-HCV.
 47. The composition according to claim 44, wherein said anti-hepatitis activity is anti-HCV.
 48. The composition according to claim 44, wherein said anti-viral activity is anti-HCV.
 49. The composition according to claim 44, wherein said anti-herpes activity is anti-HSV-1 or anti-HSV-2.
 50. A [1,8] naphthyridine derivative of Formula I and pharmaceutically acceptable salts thereof;

(I) wherein A, Z₁, Z₁′, Z₁″ and Z₂ are as defined in any one of claims 1 to 27 and 34 to 38; with the provisos that: 1) when Y is CH₂, X is O, R₁, Z₁, Z₁′, Z₁″ and Z₂ are H, and A is

then W is not 2-methoxyphenyl or 3-trifluoromethylphenyl; and 2) when Y is (CH₂)₀, X is O, R₁, Z₁, Z₁′, Z₁″ and Z₂ are H, and A is

then W is not phenyl, 3-trifluoromethylphenyl or 3-pyridinyl.
 51. A [1,8] naphthyridine derivative of Formula I and pharmaceutically acceptable salts thereof;

wherein A, Z₁, Z₁′, Z₁″ and Z₂ are as defined in claim 28; provisos that: 1) when Y is CH₂, X is O, R₁, Z₁, Z₁′, Z_(1″ and Z) ₂ are H, and A is

then W is not 2-methoxyphenyl or 3-trifluoromethylphenyl; and 2) when Y is (CH₂)₀, X is O, R₁, Z₁, Z₁′, Z₁″ and Z₂ are H, and A is

then W is not phenyl, 3-trifluoromethylphenyl or 3-pyridinyl.
 52. A [1,8] naphthyridine derivative selected from the group consisting of: [1,8] naphthyridine-2-carboxylic acid benzylamide (Compound #2); [1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamide (Compound #3); [1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamide (Compound #4); [1,8] naphthyridine-2-carboxylic acid 2,4,6-trimethoxy-benzylamide (Compound #5); [1,8] naphthyridine-2-carboxylic acid 2,3-dimethoxy-benzylamide (Compound #6); [1,8] naphthyridine-2-carboxylic acid 2,4-dimethoxy-benzylamide (Compound #7); [1,8] naphthyridine-2-carboxylic acid 2-isopropoxy-benzylamide (Compound #8); [1,8] naphthyridine-2-carboxylic acid [2-(2-methoxyphenyl)ethyl]-amide (Compound #11); [1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide (Compound #12); [1,8] naphthyridine-2-carboxylic acid (pyridin-2-ylmethyl)-amide (Compound #13); (1,8] naphthyridine-2-carboxylic acid pyridin-4-ylamide (Compound #14); [1,8] naphthyridine-2-carboxylic acid pyridin-2-ylamide (Compound #15); [1,8] naphthyridine-2-carboxylic acid 2-fluoro-benzylamide (Compound #16); [1,8] naphthyridine-2-carboxylic acid 2-chloro-benzylamide (Compound #17); [1,8] naphthyridine-2-carboxylic acid 2-trifluoromethoxy-benzylamide (Compound #18); [1,8] naphthyridine-2-carboxylic acid (3-nitrophenyl)-amide (Compound #19); N-(5,7-dimethyl-[1,8] naphthyridin-2-yl)-2-(2-methoxyphenyl)-acetamide (Compound #20); [1,8] naphthyridine-2-carboxylic acid benzyloxyamide (Compound #21); [1,8] naphthyridine-2-carboxylic acid thiazol-2-ylamide (Compound #22); [1,8] naphthyridine-2-carboxylic acid benzothiazol-2-ylamide (Compound #23); [1,8] naphthyridine-2-carboxylic acid (2-fluoro-phenyl)-amide (Compound #24); [1,8] naphthyridine-2-carboxylic acid (2-methoxy-benzyl)-methyl-amide (Compound 25); [1,8] naphthyridine-2-carbothioic acid 2-methoxy-benzylamide (Compound #26); and (2-methoxy-benzyl)-[1,8]naphthyridine-2-carboxamidine trifluoroacetate (Compound #27).
 53. The naphthyridine derivative of claim 52 wherein said derivative is in the form of the (+) enantiomer, the (−) enantiomer or mixture of the (+) and (−) enantiomer including racemic mixture.
 54. A [1,8] naphthyridine derivative selected from the group consisting of (+)-[1,8] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamide (Compound #9); and (−)-[1,8] naphthyridine-2-carboxylic acid 2-sec-butoxy-benzylamide (Compound #10).
 55. A [1,8] naphthyridine derivative selected from the group consisting of; [1,8] naphthyridine-2-carboxylic acid benzylamide (Compound #2); [1,8] naphthyridine-2-carboxylic acid 4-methoxy-benzylamide (Compound #3); [1,8] naphthyridine-2-carboxylic acid 3-methoxy-benzylamide (Compound #4); [1,8] naphthyridine-2-carboxylic acid 2,4,6-trimethoxy-benzylamide (Compound #5); [1,8] naphthyridine-2-carboxylic acid (pyridin-3-ylmethyl)-amide (Compound #12); [1,8] naphthyridine-2-carboxylic acid 2-fluoro-benzylamide (Compound #16); [1,8] naphthyridine-2-carboxylic acid 2-chloro-benzylamide (Compound #17); and (2-methoxy-benzyl)-[1,8]naphthyridine-2-carboxamidine trifluoroacetate (Compound #27). 